Abstracts

RATIONALE: Kainate is a powerful convulsant and epileptogenic agent often used to produce a model for human temporal lobe epilepsy. However, the precise molecular target through which kainate acts is uncertain because the neurotoxin is a nonselective agonist of AMPA and kainate receptors. Here we used ATPA, a tert-butyl analog of AMPA that is a highly selective agonist of GluR5 kainate receptors, to clarify the pharmacological mechanisms underlying the seizure-inducing activity of kainate. ATPA binds to GluR5 kainate receptors at [gt]1000-fold lower concentrations than to AMPA receptors. Nevertheless, to exclude the possibility that the actions of ATPA are due to interactions with AMPA receptors, control experiments were carried out with AMPA. ATPA was infused directly into the basolateral amygdala where GluR5 kainate receptors have been shown to mediate enduring synaptic facilitation, which may underlie both the acute seizure and epileptogenic effects of kainate.
METHODS: Rats were implanted with a 26- or 31-gauge stainless steel infusion cannula into the basolateral amygdala and a bipolar depth electrode into the contralateral basolateral amygdala for depth EEG recording. Screw electrodes were placed over the frontal cortex and cerebellum for surface EEG recording. After at least a 7 to 10 day recovery period, an ATPA or AMPA solution (1 - 40 nmol/5 [mu]l in sterile saline) was infused over 5 min. The animals were monitored for seizure activity by observation and EEG over the ensuing 2 months. At the end of the monitoring period, some animals underwent the intravenous (i.v.)-pentylenetetrazol (PTZ) seizure threshold test.
RESULTS: ATPA caused acute seizure activity in all 14 treated animals. Seven of these animals exhibited prolonged ([gt]30 min) status epilepticus-like generalized convulsions ([dsquote]SE animals[dsquote]). The remainder exhibited self-limited limbic seizures of various stages (modified Racine Scale, stages 1-4; [dsquote]LS animals[dsquote]). Three of the ATPA SE animals showed spontaneous limbic seizures (stage 3 or greater) over the subsequent 2 month monitoring period, as did 1 of the ATPA LS animals. AMPA also caused acute seizures in all 9 treated animals. However, in contrast to ATPA, only 1 of 5 AMPA SE animals and 0 of 4 AMPA LS animals demonstrated spontaneous seizures over the next 2 months. The i.v.-PTZ seizure threshold test also indicated a higher seizure susceptibility in ATPA-treated animals.
CONCLUSIONS: Selective activation of GluR5 kainate receptors in the amygdala with ATPA induces limbic seizure activity, and in some cases status epilepticus. In addition, animals experiencing ATPA-induced seizures may go on to exhibit persistent spontaneous seizures. Our results suggest that this can occur even in animals that do not experience SE. AMPA receptor activation also induces seizure activity but is less likely to result in persistent spontaneous seizures. We conclude that the delayed epileptogenic effect of kainate may be related specifically to activation of GluR5 kainate receptors.
[Supported by: NINDS]